Derivatives of 4-methyl 6-phenyl pyridazine, active on the central nervous system

ABSTRACT

The present invention relates to derivatives of 4-methyl 6-phenyl pyridazine of formula:    &lt;IMAGE&gt;  (I)  in which R is OH or H, R1 is H or   &lt;IMAGE&gt;   n being 0 or 1, X being H, Y being H or alkyl or X and Y forms an ethylene or oxoethylene group; it also relates to a process for preparing the products of formula (I) and to drugs containing at least one product of formula (I).

This is a divisional of copending application Ser. No. 405,169, filed onAug. 4, 1982 now U.S. Pat. No. 4,576,946.

For numerous years, derivatives of pyridazine have been proposed asdrugs. In a large number of cases, these are substances active on thecardiovascular system, presenting in particular an antihypertensive orvasodilator effect. More rarely, an anti-inflammatory and analgesicaction has been mentioned among pyridazine derivatives. Finally, FrenchPat. No. 2 141 697 describes a family of products of general formula:##STR3## where R₁ represents hydrogen or a lower alkyl group

Ar represents an aromatic radical

R₂ designates a ##STR4## in which n=2 or 3 and Y and Z represent a loweralkyl group or ##STR5## constitutes a heterocyclic radical.

These compounds are characterized by a psychotherapeutic action ofpsychotonic type.

A subsequent study of the compound where R₁ =CH₃, Ar=phenyl and ##STR6##which has received the International Common Denomination "Minaprine",has shown that it is question of a psychotherapeutic action of noveltype which has been designated by "disinhibitory" activity. Furthermore,at doses higher than 100 mg/kg per os, this product shows itself to beconvulsivant.

It has now been found that certain 6-phenyl 4-methyl 3-amino pyridazineshave the same pharmacological and biochemical properties as minaprine,whilst being less toxic and having virtually no convulsivant action.

The invention therefore relates to a family of derivatives of pyridazineof the general formule (I): ##STR7## in which: R is H or OH

R₁ represents H or the ##STR8## where n=0 or 1 X=H

Y=H or lower alkyl (1 to 4 carbon atoms) or X and Y taken together forman ethylene or oxyoethylene group, with the following conditions:

X+Y represents an ethylene group only when R represents OH,

n can be equal to 1 only if X+Y represents an ethylene group.

The present invention also relates to the acid addition salts of thecompounds of formula (I),

It also relates to a process for preparing the various compounds offormula (I) as well as to the application thereof in therapeutics.

Compounds (I) are generally obtained from a suitably substituted3-chloro pyridazine.

When R₁ is ##STR9## there is reacted on the 3-chloro pyridazine acompound ##STR10## in which Y has the meaning indicated above and X'represents hydrogen or X' and Y together represent an ethylene group.

Reaction between the chlorinated derivative and the amine is generallyeffected by heating within a suitable solvent such as an alcohol mostoften at temperature of boiling of the solvent. The duration of thereaction varies from a few hours to several days depending on the natureof the reagents employed. When the reaction proves to be too slow, itmay be catalysed by addition of a small quantity of powdered copper.

The reaction is effected in the presence of a hydracid acceptor intendedto fix the hydrochloric acid formed in the reaction. An excess of theamine is most often used as such.

Isolation of compound (I) is effected by taking up in water andextraction with a suitable solvent such as ethyl acetate.

When X and Y taken together represent an oxo ethylene group, one hasaccess to the corresponding compounds (I) from the compound (I) in whichX and Y are equal to H. ##STR11##

By action of a haloacetyl halide within an inert solvent such asdichloromethane and in the presence of an alkaline agent such as aqueoussodium hydroxide at a temperature of between -10° and 0° C., thetertiary amine 2 is obtained. The latter, by action of an alkalinealcoholate such as sodium methylate within methanol at the boilingtemperature of the solvent, leads to compound (I) in which X and Yrepresent an oxo ethylene group. The latter is isolated in the form of asalt such as the hydrochloride.

Similarly, by replacing the haloacetyl halide by ethyl bromoacetate andby operating at reflux of a solvent such as dimethylformamide in thepresence of an organic base such as triethylamine, the tertiary amine 3is obtained.

After saponification of the ester function in acid medium, for exampleby hydrochloric acid, the expected compound (I) is directly obtained [Xand Y representing ##STR12## isolated in the form of salt of the acidused. ##STR13##

If n=1, compounds (I) are obtained from the corresponding compound wheren=O by oxidation particularly by action of a per-acid such as parachloro perbenzoic acid within an inert solvent such as chloroform and ata temperature not exceeding 20° C.

When R₁ =H, it is not possible directly to obtain the 3-amino pyridazinefrom the corresponding chlorinated derivative.

In this case, the 3-hydrazino derivative obtained by action at reflux ofa large excess of hydrazine on the corresponding chlorinated derivativeis employed as intermediary. Hydrogenated in the presence of Raneynickel within a suitable solvent, it leads to the correspondingderivatives (I) R₁ =H.

Finally, in all cases when the phenyl in 6 position of the cycle ofpyridazine is substituted by an OH group (R=OH), it is preferable toprepare, according to the methods indicated previously, thecorresponding compound (I) where the phenyl group bears an alkoxysubstituent in the same position then to dealkylate this compound by aknown method, for example by action of the hydrobromic acid within theacetic acid at reflux.

Compounds (I) thus obtained may be salified in conventional manner byaction of the acid on a hot solution of the base, the solvent beingchosen so that the salt crystallizes by cooling.

The 3-chloro pyridazines used as starting product are obtained from thecorresponding 2H 3-pyridazones by action of an excess of phosphorusoxychloride.

The 2H 3-pyridazones are known or may be obtained by known processessuch as the action of hydrazine on γ ketonic acids or derivativesthereof.

The following non-limiting examples are given by way of illustration ofthe present invention.

EXAMPLE 1 3-[2-(2-HYDROXY ETHYLAMINO)ETHYLAMINO]4-METHYL6-PHENYLPYRIDAZINE, DIHYDROCHLORIDE (CM 30311) R=H; R₁ =CH₂ CH₂ NH--CH₂ CH₂ OH

A mixture of 7.7 g of 3-chloro 4-methyl 6-phenyl pyridazine and 15 g ofN-(2-hydroxy ethyl)ethylenediamine in 50 ml of n-butanol in the presenceof 2 g of powdered copper, is taken to reflux for 48 hours. The reactionmixture is poured into 100 ml of water and extracted with ether.

The ethereal phase is extracted with a solution of sulfuric acid SN. Theaqueous phase is rendered alkaline by addition of sodium hydroxide inpastille form.

The crystals are drained and recrystallized in the isopropylether-isopropanol mixture. m.p.: 91° C.

Dihydrochloride: 3.9 g of the base are dissolved in hot isopropanol then2.44 ml of concentrated solution of hydrochloric acid are added; bycooling, the hydrochloride crystallizes. It is drained andrecrystallized in isopropanol. m.p.: 144° C.

By operating as in Example 1, but by replacing the N-(2-hydroxyethyl)ethylene diamine by an equivalent quantity of N₁ -ethyl N₁(2-hydroxy ethyl)ethylenediamine, the 3-{2-[N-ethyl(2-hydroxyethylamino)]ethylamino}4-methyl 6-phenyl pyridazine (SR 95084) isobtained in the same way, isolated in the form of dihydrochloride; veryhygroscopic product decomposing from 140° C.

EXAMPLE 2 3-[2-(3-OXO 4-MORPHOLINYL)ETHYLAMINO]4-METHYL 6-PHENYLPYRIDAZINE, HYDROCHLORIDE (CM 30488) R=H; ##STR14##

5.4 g of CM 30311 (Example 1) are dissolved in 100 ml of dichloromethanethen a solution of 8 g of sodium hydroxide in 100 m of water, is added.The mixture is cooled to -10°, -5° C. and 2.2 g of chloroacetyl chlorideare added drop by drop with vigorous stirring.

Stirring is continued for 12 hours then the product is evaporated todryness. The residue is dissolved in 50 ml of anhydrous methanol and asolution of sodium methylate obtained by action of 0.46 g of sodium on50 ml of methanol is added. The product is heated to reflux for 6 hoursthen evaporated to dryness. The residue is taken up in water andextracted with ethyl acetate.

The solution is dried and evaporated to dryness; an oil is obtained.

Hydrochloride: The base is dissolved in the minimum of hot isopropanoland an equivalent of concentrated aqueous solution of hydrochloric acidis added. Ether is added and the product is left to crystallize. m.p.:190°-191° C.

EXAMPLE 3 3-[2-(2-OXO 4-MORPHOLINYL)ETHYLAMINO]4-METHYL 6-PHENYLPYRIDAZINE, DIHYDROCHLORIDE (CM 30489) R=H; ##STR15##

2.7 g of CM 30311 (Example 1) are dissolved in 50 ml ofdimethylformamide and 1 g of triethylamine and 1.7 g of ethylbromoacetate are added. The product is taken to reflux for 1 hour. Wateris added, the product is rendered alkaline and extracted with ethylacetate. The solvent is evaporated to dryness and chromatographed oversilica column. By eluting with ethyl acetate, a yellowish oil isobtained.

1 g of this oil is dissolved in 20 ml of aqueous solution of 3Nhydrochloric acid and the product is taken to reflux for 14 hours. Thesolution is washed with ether, then the aqueous phase is evaporated todryness. The residue crystallizes in ether, m.p.: 170°-2° C.

EXAMPLE 4 3-(2-MORPHOLINO ETHYLAMINO) 4-METHYL 6-(4-HYDROXYPHENYL)PYRIDAZINE DIHYDROBROMIDE (CM 30366) R=4-OH; ##STR16## (a)3-(2-Morpholino ethylamino) 4-methyl 6-(4-methoxy phenyl) pyridazine

Operation is carried out as in Example 1, replacing the N-(2-hydroxyethyl) ethylenediamine by an equivalent quantity of 2-morpholinoethylamine and the 3-chloro 4-methyl 6-phenyl pyridazine by acorresponding quantity of 3-chloro 4-methyl 6-(4-methoxy phenyl)pyridazine.

In the same way, the product is isolated in the form of dichlorohydrate.m.p. 225° C.

(b) CM 30366

19 g of the base released from the hydrochloride obtained hereinabove,in 150 ml of a 2-1 (vol/vol) mixture of 48% hydrobromic acid and aceticacid are taken to reflux for 6 hours.

The product is evaporated to dryness. A brown oil remains whichcrystallizes in an ethanol-ether mixture. The crystals are drained andrecrystallized in ethanol at 95; m.p. 162° C.

By operating as in Example 4a) from the 3-chloro 4-methyl 6-(2- or3-methoxy phenyl) pyridazines then by demethylating the products thusobtained according to the method of Example 4b), the following arerespectively obtained:

3-(2-morpholino ethylamino) 4-methyl 6-(2-hydroxy phenyl) pyridazine (SR95070) isolated in the form of dihydrobromide; m.p. 170° C.(decomposition).

3-(2-morpholino ethylamino) 4-methyl 6-(3-hydroxy phenyl) pyridazine (SR95082) isolated in the form of dihydrobromide; m.p.: 180° C. withdecomposition.

EXAMPLE 5 N-OXIDE OF 3-(2-MORPHOLINO ETHYLAMINO 4-METHYL 6-PHENYLPYRIDAZINE (CM 30490) (I) R=H; ##STR17##

1.5 g of 2-morpholino 3-ethylamino 4-methyl 6-phenyl pyridazine aredissolved in 100 ml of anhydrous chloroform. 0.90 g of para chloroperbenzoic acid is then added and the product is left for 48 hours atambient temperature. The organic solution is washed with an 10% aqueoussolution of sodium bicarbonate. The solution is dried and evaporated todryness; the residue crystallizes by addition of ether. The product isrecrystallized in the mixture of ethyl acetate-hexane.

1 g of crystals is obtained. m.p. with decomposition from 150° C.

EXAMPLE 6 3-AMINO 4-METHYL 6-PHENYL PYRIDAZINE (HYDROCHLORIDE) (CM30465) (I) R=R₁ =H (a) 3-Hydrazino 4-methyl 6-phenyl pyridazine

The mixture of 5 g of 3-chloro 4-methyl 6-phenyl pyridazine and 12 ml ofhydrazine hydrate is taken to reflux. After one hour thirty minutes, thereaction medium is left to cool. A solid separates, which is drained andwashed with a little water. The product is recrystallized in the mixtureof isopropanol-isopropyl ether. Weight 4.5 g. m.p.: 162° C.

(b) CM 30465

6.5 g of the preceding derivative are dissolved in the minimum ofmethanol and 2.5 g of Raney nickel are added. Hydrogenation is effectedunder a pressure of 5 atmospheres for 48 hours. The catalyst is filteredand evaporated to dryness. The residue is recrystallized in a mixture ofisopropanol-isopropyl ether. Weight 5.25 g. m.p. 130°-2° C.

Hydrochloride: To 2 g of base dissolved in the minimum of isopropanolare added 1.2 equivalents of gaseous hydrochloric acid then the productis precipated by addition of ether. A white powder is obtained (1.7 g).m.p. 172°-4° C.

By operating as in Example 6a) from 3-chloro 4-methyl 6-(4-methoxyphenyl) pyridazine, the corresponding 3-hydrazino derivative isobtained. The latter treated as in Example 6b) furnishes thecorresponding 3-amino derivative.

Finally, by demethylation as in Example 4b), 3-amino 4-methyl6-(4-hydroxy phenyl) pyridazine (SR 95087) is obtained, isolated in theform of hydrobromide; m.p.: 260° C. (decomposition).

The products according to the invention were subjected topharmacological tests with a view to determining their activity on thecentral nervous system and the toxicity thereof.

ACUTE TOXICITY

The products to be studied were administered by the intraperitonealroute in increasing doses to batches of 10 mice. The mortality provokedby the products studied was noted during the 24 hours followingadministration of the product.

From the results obtained, the lethal dose 50, i.e. the dose provokingthe death of 50% of the animals studied, is determined for each of theproducts studied.

During the same experiments, the convulsivant threshold dose of theproduct is also noted, i.e. the minimum dose for which a convulsivantactivity begins to show.

The results obtained are shown in Table I. This Table shows by way ofcomparison 2 products described in French Pat. No. 2 141 697 citedabove: ##STR18##

The figures shown in Table I indicate that the products according to theinvention present a toxicity and a convulsivant action much less thanthose of the reference products.

                  TABLE I    ______________________________________                          Convulsivant threshold dose    Compound            LD.sub.50 (mg/kg; i.p.)                          (mg/kg; i.p.)    ______________________________________    Minaprine            63 (52-77)     35    CM 30073            19 (11-35)     5    CM 30311            >200          200    CM 30366            >200          200    SR 30488            >300          300    SR 30465            226           200    SR 30490            >200          300    SR 95070            >200          200    SR 95082            >200          >200    SR 95084            100 < LD.sub.50 < 200                          200    SR 95087            >200          >200    ______________________________________

ANTIDEPRESSANT ACTIVITY Despair reaction

This test was carried out on the female mouse, CDI (Charles River),weighing 18 to 23 g, according to the method described by Porsolt(Archives Internationales de Pharmacodynamie, 1977, 229, 327-336).

The principle of this test is as follows: when a mouse is placed in anarrow recipient filled with water, it struggles, then, after 2 to 4mins., it becomes still and floats on its stomach, its back rounded, itsrear paws drawn up under its body and it makes only a few movementsnecessary for holding its head out of the water. This is the so-calleddespair reaction.

Certain psychotherapeutic agents, particularly antidepressants, extendthe time during which the mouse struggles.

The following protocol was chosen: The products to be studied wereadministered by the i.p. route 1 hour before the test. For the test, theanimals are placed in a narrow recipient (10×10×10 cm) filled with waterup to a height of 6 cm, the temperature of the water being 24° C.±2° C.The animals are left 6 minutes in the water and the time when the animalremains immobile between the 2nd and the 6th minute is measured--theshorter this time, the more the substance is active.

Each substance was studied on a batch of 10 mice. The results are theaverage of at least two experiments.

Antagonism of the ptosis induced by reserpine

This test, described by GOURET (Journal de Pharmacologie (Paris), 1973,4(1), 105-128), was carried out on the female mouse CDI (Charles River)weighing 20±1 g. The reserpine provokes a ptosis one hour afterintravenous administration thereof; certain antidepressants oppose thisptosis.

The following protocol was chosen: The substances to be studied wereadministered by the i.p. route. The reserpine is administeredsimultaneously by the intravenous route at the dose of 2 mg/kg. One hourafter administration of the reserpine, the number of animals notpresenting ptosis is noted.

This test was carried out on batches of 10 mice, the results areexpressed in percentage of animals not presenting ptosis and are theaverage of at least two experiments.

The results obtained with the products of the invention are shown inTable II. By way of comparison, the results obtained with the twoproducts of the prior art, Minaprine and CM 30073, have also beenindicated.

                  TABLE II    ______________________________________    Antidepressant activity            Antagonism of the ptosis                            "Behavioral Despair"            induced by reserpine                            % of reduction of the    Compounds            (ED.sub.50, mg/kg; i.p.)                            duration of immobilisation    ______________________________________    Minaprine            5 (4-7)         10 mg/kg: -35%**    CM 30073            1 mg/kg: 30%    --            5 mg/kg: 60%            product too toxic at            higher doses    CM 30366            12 (11-15)      10 mg/kg: -31%**    CM 30465            8.6 (8.3-9)     10 mg/kg: -24%**    SR 30488            20 (13-31)      --    SR 30490            ≅50   --    ______________________________________

DOPAMINOMIMETIC ACTIVITY

The depaminomimetic activity of the products of the invention wasstudied on the striatal dopaminergic receptors of the mouse according tothe technique described by P. PROTAIS and J. COSTENTIN, Journal dePharmacologie (Paris), 7, 251-255 (1976).

The unilateral lesion of the nigrostriatal dopaminergic neurones inducesa hypersensitivity of the receptors of the dopamine at the level of thestriatum. The resulting asymmetry is revealed by rotations of the animalin the direction contralateral to the most intensely stimulatedreceptors.

After administration of the products to be studied by theintraperitoneal route, the number of rotations made by the animal iscounted for a period of 2 minutes.

The results are expressed in the form of percentage of the variationswith respect to the controls not having received the product to bestudied.

The results obtained with various products of the invention are shown inTable III which also shows the results of the 2 comparison products:Minaprine and CM 30073.

Tables I, II and III show that the compounds representative of thepresent invention have, overall, an antidepressant and dopaminomimeticactivity of the same order of size as that of minaprine.

With respect to minaprine and especially to CM 30073, the productsrepresentative of the present invention are only slightly toxic and havevirtually no convulsivant activity.

The new compounds of the present invention may thus be used intherapeutics for all disorders of the psychomotor behaviour.

                  TABLE III    ______________________________________                          Average number of ipsilateral              Doses μmoles/                          rotations in 2 minutes    COMPOUNDS kg; i.p.    % with respect to controls    ______________________________________    Minaprine 5.3         -91%    CM 30073  5.3           0%    CM 30311  5.3         -146%    CM 30366  5.3         -111%    CM 30465  5.3         -89%    CM 30488  5.3         -90%    CM 30489  5.3         -97%    SR 95070  5.3         -89%    ______________________________________

They may be prescribed inter alia for hyperkinesis in the child, for themasked depression in the adult, for serious depressive states, fordepression in the elderly and for disorders in the memory and insenescence.

These products may be administered by the oral route or by injectableroute. The pharmaceutical compositions may be solid or liquid and be,for example, in the form of tablets, capsules, granulates, suppositoriesor injectable preparations.

Dosage may vary to large proportions, particularly according to the typeand seriousness of the disorder to be treated and depending on the modeof administration. In the adult, by the oral route, it is most oftenbetween 0.010 g and 0.500 g possibly distributed in several doses.

By way of example, the following Galenic preparation may be indicated:

    ______________________________________    Tablets    ______________________________________    CM 30465            200 mg    Microcrystalline cellulose                        100 mg    Lactose             197 mg    Magnesium stearate   3 mg                        500 mg    ______________________________________

What is claimed is:
 1. Compounds of 4-methyl 6-phenyl pyridazine of theformula: ##STR19## in which: R is H or OH andR₁ represents H and thepharmaceutically acceptable acid addition salts thereof.
 2. Thecompounds of claim 1, which are the addition salts of the compounds offormula (I) with a pharmaceutically acceptable acid.
 3. A pharmaceuticalcomposition for the treatment of depressive states which contains atleast one product of claim
 1. 4. A pharmaceutical composition whichcontains from 0.01 g to 0.500 g of at least one product according toclaim
 1. 5. A pharmaceutical composition for the treatment of depressivestates which contains at least one product of claim
 2. 6. Apharmaceutical composition for the treatment of depressive states whichcontains from 0.01 g to 0.500 g of at least one product of claim 2.